Mycobacterium tuberculosis (M. tb) is a global public health challenge. In 2012, the World Health Organization (WHO) reported 8.6 million new cases and 1.3 million deaths caused by M. tb. Tuberculosis (TB) is the most deadly infectious disease worldwide and remains a challenge, especially in sub Saharan Africa, Russia and Eastern Europe. The emergence of multiple drug resistant (MDR) and extensively drug resistant (XDR) strains with the high number of HIV cases highlight the pressing need for novel therapeutic approaches.2a 
In 2013, Zumla et al. reported that “no new TB drug classes have been developed or approved for drug susceptible TB since the current 6-month four-drug combination was introduced in the 1970s.”2c However, it was also stated that “significant effort is being invested in drug development for drug susceptible TB” and that “there is growing awareness of the need for drugs that can kill M. tuberculosis in its different physiological states.”2c Many of the promising new molecules in development are either repurposed drug compounds or new derivatives of known anti-mycobacterial drugs.2c-e Moreover, many of these (new) drugs specifically target the cell wall biosynthesis, but none are reported to target intracellular lipid metabolism.
Primo-infection with M. tb leads to the formation of granulomas in the lung, where some of the infected macrophages accumulate lipids in lipid bodies (LB) giving the cells a foamy appearance.3 In such foamy macrophages (FM), bacilli accumulate lipids and can persist in a non-replicating state for decades, but can also be reactivated to cause acute disease.4 A better understanding of how bacilli persist inside lipid-rich FM is needed to find new ways to fight the disease. To persist inside the FM, M. tb hydrolyzes host lipids into fatty acids that are reused as lipid reserves within intracytoplasmic lipid inclusions (ILI). Recent results suggest a direct link between the presence of ILI in mycobacteria and their inability to divide. The latter may be of central importance for mycobacterial persistence within granulomas. Over the past ten years, lipolytic enzymes, which are responsible for the release of long-chain fatty acids, have become a focus of research.5a These enzymes, strongly involved in the host-pathogen cross-talk, play several roles in the physiopathology of the disease during both the active and persistent phases of infection. Although their role in the control of host lipid breakdown and ILI consumption during infection is documented, the molecular mechanisms involved in these processes remain elusive. Recently, these enzymes have become mycobacterial drug targets (Canaan and others).5b-d Accordingly, finding ways to inhibit their activity could pave the way for discovery of new modalities for the treatment of TB as well as potentially other uses.
Phosphorus fluorides [RP(O)F(OR)] such as DIFP [(iPrO)2P(O)F)] have become important tools in investigating serine hydrolase biochemistry. However, they are very reactive which makes them unstable in aqueous solution and somewhat promiscuous in their interaction with enzymes. None-the-less, several very useful affinity probes based on phosphorus fluorides have been developed.18 Phenyl phosphonate esters [RP(O)(OPh)2] are another example of irreversible hydrolase inhibitor.19 They are somewhat less reactive than the fluorides, although the reactivity can be tuned by substituents on the phenyl leaving group (e.g., NO2). Due to the relatively simple structure of such inhibitors [R—P(O)X(OR), X=F or OAr] structural modifications for SAR can be somewhat limited. Other M. tb lipase inhibitors are derivatives of the β-lactone anti-obesity drug Orlistat. They are, in some cases potent, but can be less non-specific.